Adjia Hamadjida

Effects of Unilateral Motor Cortex Lesion on Ipsilesional Hand's Reach and Grasp Performance in Monkeys: Relationship With Recovery in the Contralesional Hand

Manual dexterity, a prerogative of primates, is under the control of the corticospinal (CS) tract. Because 90-95% of CS axons decussate, it is assumed that this control is exerted essentially on the contralateral hand. Consistently, unilateral lesion of the hand representation in the motor cortex is followed by a complete loss of dexterity of the contralesional hand. During the months following lesion, spontaneous recovery of manual dexterity takes place to a highly variable extent across subjects, although largely incomplete. In the present study, we tested the hypothesis that after a significant postlesion period, manual performance in the ipsilesional hand is correlated with the extent of functional recovery in the contralesional hand. To this aim, ten adult macaque monkeys were subjected to permanent unilateral motor cortex lesion. Monkeys manual performance was assessed for each hand during several months postlesion, using our standard behavioral test (modified Brinkman board task) that provides a quantitative measure of reach and grasp ability. The ipsilesional hands performance was found to be significantly enhanced over the long term (100-300 days postlesion) in six of ten monkeys, with the six exhibiting the best, though incomplete, recovery of the contralesional hand. There was a statistically significant correlation (r = 0.932; P < 0.001) between performance in the ipsilesional hand after significant postlesion period and the extent of recovery of the contralesional hand. This observation is interpreted in terms of different possible mechanisms of recovery, dependent on the recruitment of motor areas in the lesioned and/or intact hemispheres.

Autologous adult cortical cell transplantation enhances functional recovery following unilateral lesion of motor cortex in primates: a pilot study.

BACKGROUND:Although cell therapy is a promising approach after cerebral cortex lesion, few studies assess quantitatively its behavioral gain in nonhuman primates. Furthermore, implantations of fetal grafts of exogenous stem cells are limited by safety and ethical issues. OBJECTIVE:To test in nonhuman primates the transplantation of autologous adult neural progenitor cortical cells with assessment of functional outcome. METHODS:Seven adult macaque monkeys were trained to perform a manual dexterity task, before the hand representation in motor cortex was chemically lesioned unilaterally. Five monkeys were used as control, compared with 2 monkeys subjected to different autologous cells transplantation protocols performed at different time intervals. RESULTS:After lesion, there was a complete loss of manual dexterity in the contralesional hand. The 5 “control” monkeys recovered progressively and spontaneously part of their manual dexterity, reaching a unique and definitive plateau of recovery, ranging from 38% to 98% of prelesion score after 10 to 120 days. The 2 “treated” monkeys reached a first spontaneous recovery plateau at about 25 and 40 days postlesion, representing 35% and 61% of the prelesion performance, respectively. In contrast to the controls, a second recovery plateau took place 2 to 3 months after cell transplantation, corresponding to an additional enhancement of functional recovery, representing 24% and 37% improvement, respectively. CONCLUSIONS:These pilot data, derived from 2 monkeys treated differently, suggest that, in the present experimental conditions, autologous adult brain progenitor cell transplantation in a nonhuman primate is safe and promotes enhancement of functional recovery.

Behavioral assessment of manual dexterity in non-human primates.

The corticospinal (CS) tract is the anatomical support of the exquisite motor ability to skillfully manipulate small objects, a prerogative mainly of primates1. In case of lesion affecting the CS projection system at its origin (lesion of motor cortical areas) or along its trajectory (cervical cord lesion), there is a dramatic loss of manual dexterity (hand paralysis), as seen in some tetraplegic or hemiplegic patients. Although there is some spontaneous functional recovery after such lesion, it remains very limited in the adult. Various therapeutic strategies are presently proposed (e.g. cell therapy, neutralization of inhibitory axonal growth molecules, application of growth factors, etc), which are mostly developed in rodents. However, before clinical application, it is often recommended to test the feasibility, efficacy, and security of the treatment in non-human primates. This is especially true when the goal is to restore manual dexterity after a lesion of the central nervous system, as the organization of the motor system of rodents is different from that of primates1,2. Macaque monkeys are illustrated here as a suitable behavioral model to quantify manual dexterity in primates, to reflect the deficits resulting from lesion of the motor cortex or cervical cord for instance, measure the extent of spontaneous functional recovery and, when a treatment is applied, evaluate how much it can enhance the functional recovery. The behavioral assessment of manual dexterity is based on four distinct, complementary, reach and grasp manual tasks (use of precision grip to grasp pellets), requiring an initial training of adult macaque monkeys. The preparation of the animals is demonstrated, as well as the positioning with respect to the behavioral set-up. The performance of a typical monkey is illustrated for each task. The collection and analysis of relevant parameters reflecting precise hand manipulation, as well as the control of force, are explained and demonstrated with representative results. These data are placed then in a broader context, showing how the behavioral data can be exploited to investigate the impact of a spinal cord lesion or of a lesion of the motor cortex and to what extent a treatment may enhance the spontaneous functional recovery, by comparing different groups of monkeys (treated versus sham treated for instance). Advantages and limitations of the behavioral tests are discussed. The present behavioral approach is in line with previous reports emphasizing the pertinence of the non-human primate model in the context of nervous system diseases2,3.

Different Patterns of Cortical Inputs to Subregions of the Primary Motor Cortex Hand Representation in Cebus apella

The primary motor cortex (M1) plays an essential role in the control of hand movements in primates and is part of a complex cortical sensorimotor network involving multiple premotor and parietal areas. In a previous study in squirrel monkeys, we found that the ventral premotor cortex (PMv) projected mainly to 3 regions within the M1 forearm representation [rostro-medial (RM), rostro-lateral (RL), and caudo-lateral (CL)] with very few caudo-medial (CM) projections. These results suggest that projections from premotor areas to M1 are not uniform, but rather segregated into subregions. The goal of the present work was to study how inputs from diverse areas of the ipsilateral cortical network are organized within the M1 hand representation. In Cebus apella, different retrograde neuroanatomical tracers were injected in 4 subregions of the hand area of M1 (RM, RL, CM, and CL). We found a different pattern of input to each subregion of M1. RM receives inputs predominantly from dorsal premotor cortex, RL from PMv, CM from area 5, and CL from area 2. These results support that the M1 hand representation is composed of several subregions, each part of a unique cortical network.

Comparison of functional recovery of manual dexterity after unilateral spinal cord lesion or motor cortex lesion in adult macaque monkeys

In relation to mechanisms involved in functional recovery of manual dexterity from cervical cord injury or from motor cortical injury, our goal was to determine whether the movements that characterize post-lesion functional recovery are comparable to original movement patterns or do monkeys adopt distinct strategies to compensate the deficits depending on the type of lesion? To this aim, data derived from earlier studies, using a skilled finger task (the modified Brinkman board from which pellets are retrieved from vertical or horizontal slots), in spinal cord and motor cortex injured monkeys were analyzed and compared. Twelve adult macaque monkeys were subjected to a hemi-section of the cervical cord (nu2009=u20096) or to a unilateral excitotoxic lesion of the hand representation in the primary motor cortex (nu2009=u20096). In addition, in each subgroup, one half of monkeys (nu2009=u20093) were treated for 30u2009days with a function blocking antibody against the neurite growth inhibitory protein Nogo-A, while the other half (nu2009=u20093) represented control animals. The motor deficits, and the extent and time course of functional recovery were assessed. For some of the parameters investigated (wrist angle for horizontal slots and movement types distribution for vertical slots after cervical injury; movement types distribution for horizontal slots after motor cortex lesion), post-lesion restoration of the original movement patterns (“true” recovery) led to a quantitatively better functional recovery. In the motor cortex lesion groups, pharmacological reversible inactivation experiments showed that the peri-lesion territory of the primary motor cortex or re-arranged, spared domain of the lesion zone, played a major role in the functional recovery, together with the ipsilesional intact premotor cortex.

Influence of anti-Nogo-A antibody treatment on the reorganization of callosal connectivity of the premotor cortical areas following unilateral lesion of primary motor cortex (M1) in adult macaque monkeys

Following unilateral lesion of the primary motor cortex, the reorganization of callosal projections from the intact hemisphere to the ipsilesional premotor cortex (PM) was investigated in 7 adult macaque monkeys, in absence of treatment (control; nxa0=xa04) or treated with function blocking antibodies against the neurite growth inhibitory protein Nogo-A (nxa0=xa03). After functional recovery, though incomplete, the tracer biotinylated dextran amine (BDA) was injected in the ipsilesional PM. Retrogradely labelled neurons were plotted in the intact hemisphere and their number was normalized with respect to the volume of the core of BDA injection sites. (1) The callosal projections to PM in the controls originate mainly from homotypic PM areas and, but to a somewhat lesser extent, from the mesial cortex (cingulate and supplementary motor areas). (2) In the lesioned anti-Nogo-A antibody-treated monkeys, the normalized number of callosal retrogradely labelled neurons was up to several folds higher than in controls, especially in the homotypic PM areas. (3) Except one control with a small lesion and a limited, transient deficit, the anti-Nogo-A antibody-treated monkeys recovered to nearly baseline levels of performance (73–90xa0%), in contrast to persistent deficits in the control monkeys. These results are consistent with a sprouting and/or sparing of callosal axons promoted by the anti-Nogo-A antibody treatment after lesion of the primary motor cortex, as compared to untreated monkeys.

Short-term effects of unilateral lesion of the primary motor cortex (M1) on ipsilesional hand dexterity in adult macaque monkeys.

Although the arrangement of the corticospinal projection in primates is consistent with a more prominent role of the ipsilateral motor cortex on proximal muscles, rather than on distal muscles involved in manual dexterity, the role played by the primary motor cortex on the control of manual dexterity for the ipsilateral hand remains a matter a debate, either in the normal function or after a lesion. We, therefore, tested the impact of permanent unilateral motor cortex lesion on the manual dexterity of the ipsilateral hand in 11 macaque monkeys, within a time window of 60xa0days post-lesion. For comparison, unilateral reversible pharmacological inactivation of the motor cortex was produced in an additional monkey. Manual dexterity was assessed quantitatively based on three motor parameters derived from two reach and grasp manual tasks. In contrast to the expected dramatic, complete deficit of manual dexterity of the contralesional hand that persists for several weeks, the impact on the manual dexterity of the ipsilesional hand was generally moderate (but statistically significant) and, when present, lasted less than 20xa0days. Out of the 11 monkeys, only 3 showed a deficit of the ipsilesional hand for 2 of the 3 motor parameters, and 4 animals had a deficit for only one motor parameter. Four monkeys did not show any deficit. The reversible inactivation experiment yielded results consistent with the permanent lesion data. In conclusion, the primary motor cortex exerts a modest role on ipsilateral manual dexterity, most likely in the form of indirect hand postural control.

Follow-up of cortical activity and structure after lesion with laser speckle imaging and magnetic resonance imaging in nonhuman primates

The nonhuman primate model is suitable to study mechanisms of functional recovery following lesion of the cerebral cortex (motor cortex), on which therapeutic strategies can be tested. To interpret behavioral data (time course and extent of functional recovery), it is crucial to monitor the properties of the experimental cortical lesion, induced by infusion of the excitotoxin ibotenic acid. In two adult macaque monkeys, ibotenic acid infusions produced a restricted, permanent lesion of the motor cortex. In one monkey, the lesion was monitored over 3.5 weeks, combining laser speckle imaging (LSI) as metabolic readout (cerebral blood flow) and anatomical assessment with magnetic resonance imaging (T2-weighted MRI). The cerebral blood flow, measured online during subsequent injections of the ibotenic acid in the motor cortex, exhibited a dramatic increase, still present after one week, in parallel to a MRI hypersignal. After 3.5 weeks, the cerebral blood flow was strongly reduced (below reference level) and the hypersignal disappeared from the MRI scan, although the lesion was permanent as histologically assessed post-mortem. The MRI data were similar in the second monkey. Our experiments suggest that LSI and MRI, although they reflect different features, vary in parallel during a few weeks following an excitotoxic cortical lesion.

Long-term motor cortical map changes following unilateral lesion of the hand representation in the motor cortex in macaque monkeys showing functional recovery of hand functions

PURPOSEnHow are motor maps modified within and in the immediate vicinity of a damaged zone in the motor cortex of non-human primates?nnnMETHODSnIn eight adult macaque monkeys subjected to a restricted chemical lesion of the hand area in the primary motor cortex (M1), motor maps were established using intracortical micro-stimulation (ICMS) techniques. The monkeys were subdivided into five animals without treatment, whereas three monkeys received an anti-Nogo-A antibody treatment.nnnRESULTSnFollowing permanent M1 injury, the lesion territory became largely non micro-excitable several months post-lesion, in spite of some recovery of hand function. Few sites within the lesion territory remained excitable, though irrespective to the degree of functional recovery. Around the lesion in M1, there was no reallocation of proximal shoulder/arm territories into distal hand functions. However, ICMS delivered at supra-threshold intensities in these proximal territories elicited digit movements. Post-lesion ICMS thresholds to elicit movements of forelimb muscle territories increased, independently from the degree of functional recovery. Further behavioural evidence for an enhancement of functional recovery promoted by the anti-Nogo-A antibody treatment is provided.nnnCONCLUSIONnThe degree of functional recovery is not related to a reorganization of motor maps within, and in the vicinity of, a M1 lesion.

Corticobulbar projections from distinct motor cortical areas to the reticular formation in macaque monkeys

Corticospinal and corticobulbar descending pathways act in parallel with brainstem systems, such as the reticulospinal tract, to ensure the control of voluntary movements via direct or indirect influences onto spinal motoneurons. The aim of this study was to investigate the corticobulbar projections from distinct motor cortical areas onto different nuclei of the reticular formation. Seven adult macaque monkeys were analysed for the location of corticobulbar axonal boutons, and one monkey for reticulospinal neurons location. The anterograde tracer BDA was injected in the premotor cortex (PM), in the primary motor cortex (M1) or in the supplementary motor area (SMA), in 3, 3 and 1 monkeys respectively. BDA anterograde labelling of corticobulbar axons were analysed on brainstem histological sections and overlapped with adjacent Nissl‐stained sections for cytoarchitecture. One adult monkey was analysed for retrograde CB tracer injected in C5‐C8 hemispinal cord to visualise reticulospinal neurons. The corticobulbar axons formed bilateral terminal fields with boutons terminaux and en passant, which were quantified in various nuclei belonging to the Ponto‐Medullary Reticular Formation (PMRF). The corticobulbar projections from both PM and SMA tended to end mainly ipsilaterally in PMRF, but contralaterally when originating from M1. Furthermore, the corticobulbar projection was less dense when originating from M1 than from non‐primary motor areas (PM, SMA). The main nuclei of bouton terminals corresponded to the regions where reticulospinal neurons were located with CB retrograde tracing. In conclusion, the corticobulbar projection differs according to the motor cortical area of origin in density and laterality.